US20080269670A1 - Skin Penetrating Touch Fasteners - Google Patents
Skin Penetrating Touch Fasteners Download PDFInfo
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- US20080269670A1 US20080269670A1 US11/739,244 US73924407A US2008269670A1 US 20080269670 A1 US20080269670 A1 US 20080269670A1 US 73924407 A US73924407 A US 73924407A US 2008269670 A1 US2008269670 A1 US 2008269670A1
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- Prior art keywords
- skin
- foam
- skin penetrating
- attachment member
- backing
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/20—Surgical instruments, devices or methods, e.g. tourniquets for vaccinating or cleaning the skin previous to the vaccination
- A61B17/205—Vaccinating by means of needles or other puncturing devices
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Definitions
- This application relates to skin penetrating touch fasteners.
- Transdermal delivery of drugs has been around for a number of years.
- Transdermal delivery of drugs offers many advantages over more traditional routes of medicating a patient, i.e. oral administration of the medication or injection methods.
- One of the advantages of transdermal administration is that it avoids the negative side effects of oral administration, for example irritation of the gastrointestinal tract (some medicines cause ulcers and gastrointestinal bleeding).
- Transdermal administration also avoids hepatic and systemic toxicity that can result from the necessarily larger doses of the drag that have to be administered orally in order to compensate for hepatic first pass metabolism of drugs absorbed through the gastrointestinal tract, and to maintain therapeutic blood levels of the drug over the dosing interval.
- transdermal delivery offers a painless, convenient, and non-invasive way to administer drugs, providing more stable blood levels with less frequent dosing because of controlled release of the medication.
- these benefits can only be achieved for a few drugs that are able to cross the barrier established by the skin, such as some cardiac drugs and hormones.
- the stratum corneum (composed of a lipid bilayers located between dead keratinocytes cells) provides the main resistance to drug delivery through the skin, limiting the transdermal route to drugs having a low molecular weight, i.e. less than 500 Daltons, and having the appropriate lipophilicity.
- drugs suitable for transdermal delivery are non-ionic, and/or have high potency, such that therapeutic effects can be achieved with small amounts of transdermal absorption.
- Other factors affecting absorption are the site of application, length of application, the addition of an absorption vehicle (penetration enhancer or enhancers), such as organic solvents like dimethyl sulfoxide (DMSO), and the integrity of the epidermal barrier.
- penetration enhancer or enhancers such as organic solvents like dimethyl sulfoxide (DMSO)
- Transdermal deliver of drugs having a molecular weight of greater than 500 Daltons requires some type of skin permeation enhancement mechanism, such as chemical penetration enhancers. Therefore, transdermal administration of drugs has generally been limited to drugs having the required physiochemical properties allowing absorption through the epidermal layer.
- Improvements in the transdermal delivery of drugs are sought, such as improvements that may lead to the applicability of transdermal delivery of drags to a broad group of medicines and higher molecular weight biomolecules.
- the disclosure features a skin attachment member, which has a backing with a first surface and a second surface.
- a plurality of skin penetrating elements extend integrally from the first surface of the backing to a distal tip.
- the skin penetrating elements are sized to avoid contact with the nerves below the epidermal skin layer.
- the skin attachment member has a foam disposed on the first surface of the backing, such that at least a portion of the foam is disposed between at least some of the skin penetrating elements.
- the foam may be, for example, polyvinyl chloride (PVC) or polyurethane (PU).
- a pharmaceutical composition is disposed within the foam.
- the pharmaceutical composition may be in the form, for example, of a cream, a gel, or a liquid.
- the pharmaceutical composition is a biomolecule.
- the biomolecule can be a hormone or an antibody.
- the pharmaceutical composition is a small molecule.
- the pharmaceutical composition can be a controlled release formulation.
- the pharmaceutical composition can further include a vehicle.
- a penetration enhancer is disposed within the foam.
- An adhesive can be disposed on a surface of the foam.
- at least a portion of the foam extends to a height greater than the height of at least some of the skin penetration elements.
- a plurality of the skin penetrating elements may extend to a height greater than the foam.
- a plurality of the skin penetrating elements have a groove extending lengthwise from the base towards the distal tip. e.g., from the base to the tip. Some of the skin penetrating elements have at least one retention barb extending from an outer side surface of the skin penetrating element.
- the base of the skin penetrating elements is a plastic resin.
- the skin penetrating elements have a height of about 0.004 to about 0.040 inches, for example, about 0.012 inches.
- the disclosure features a skin attachment member having a backing, which has a first surface and a second surface.
- a plurality of skin penetrating elements extend integrally from the first surface of the backing to a distal tip, and a foam is disposed on the first surface of the backing, such that at least a portion of the foam is disposed between at least some of the skin penetrating elements, the foam having a pharmaceutical composition disposed therein.
- the disclosure features a method of delivering a pharmaceutical composition by attaching a skin attachment member to the skin of a subject, and maintaining the skin attachment member on the skin of the subject for a time sufficient to allow at least a portion of a pharmaceutical composition to permeate the epidermis of the subject.
- the skin attachment member has a backing, which has a first surface and a second surface, and a plurality of skin penetrating elements extending integrally from the first surface of the backing to a distal tip.
- the skin penetrating elements are sized to avoid contact with nerves below the epidermal skin layer.
- a plurality of the skin penetrating elements include at least one retention barb extending from an outer side surface of the skin penetrating element.
- a foam is disposed on the first surface of the backing, such that a portion of the foam is disposed between at least some of the skin penetrating elements.
- the pharmaceutical composition is disposed within the foam.
- the method includes providing a skin penetrating enhancer.
- the skin penetrating enhancer is disposed within the foam.
- the method includes heating the skin attachment member.
- the method includes maintaining the skin attachment member on the subject for at least 2 hours, for at least 12 hours, for at least 24 hours, and for at least one week.
- FIG. 1 is a highly magnified, side view of a section of a skin attachment member, shown secured in the epidermis;
- FIG. 2 is a diagrammatic perspective view of the section of the skin attachment member of FIG. 1 ;
- FIG. 3A is a side view of the skin-penetrating element of the skin attachment member of FIG. 1 :
- FIG. 3B is another side view of the element of FIG. 3A , rotated 90 degrees relative to FIG. 3A ;
- FIG. 3C is an end view of the element of FIG. 3A taken along lines 3 C- 3 C in FIG. 3A ;
- FIG. 3D is a cross-sectional view of the element of FIG. 3A taken along lines 3 D- 3 D in FIG. 3B ;
- FIG. 4 is a perspective view of section A of FIG. 3B , showing a barb of the element of FIG. 3A :
- FIG. 5 shows an alternative embodiment of a barb
- FIG. 6A is a side view of a skin attachment member with foam attached to the upper face of a sheet form base
- FIG. 6B is a perspective view of a skin attachment member of FIG. 2A ;
- FIG. 7A is an end view of a skin attachment member having foam attached to the upper face of a sheet form base where foam extends longitudinally beyond an array of fastener elements on the upper face of the sheet form base;
- FIG. 7B is an end view of a skin attachment member having foam attached to the upper face of a sheet form base where foam extend longitudinally beyond an array of fastener elements on the tipper face of the sheet form base and having electrical elements on one or more peripheral edges;
- FIG. 8 is a cross-sectional view of a skin attachment member having foam attached to the upper face of a sheet form base, in which the height of the foam is greater than the height of the elements;
- FIG. 9 shows schematically an apparatus and process for manufacturing a skin attachment member having foam attached to the upper face of a sheet form base
- FIG. 10 shows schematically an apparatus and process for manufacturing a skin attachment member having foam attached to the upper face of a sheet form base
- FIG. 11A is a side view of the mold roll of FIG. 9 ;
- FIG. 11B is a cross-sectional view of a portion of the mold roll, taken along lines 11 B- 11 B in FIG. 11A ;
- FIG. 11C is an end view of the mold roll, taken along lines 11 C- 11 C in FIG. 11B ;
- FIG. 11D is a magnified side view of portion 11 D of the mold roll of FIG. 11A ;
- FIG. 11E shows laser machining of the mold roll
- FIG. 12 shows art alterative edge formation on a mold roll
- FIG. 13A shows the different layers of a segment of skin
- FIG. 13B is a enlarged view of the section 13 B shown in FIG. 13A ;
- FIG. 13C shows a highly magnified view of the skin attachment member with foam attached secured to the epidermis
- FIG. 13D shows a highly magnified view of the skin attachment member and attached foam with a strip of conductive material attached to a non-foam covered peripheral edge of the upper face.
- a skin attachment member 10 formed of plastic resin, includes a backing 12 having an upper face 13 and a lower face 11 , and multiple, parallel rows of integrally molded, pointed projections or elements 14 extending from backing 12 for penetrating into the epidermis 16 .
- the skin-penetrating elements 14 each, include a cone-shaped body 18 with one or more discrete barbs 20 extending from the body for securing skin attachment member 10 to epidermis 16 .
- the length of elements 14 is selected such that the elements do not penetrate so far into the skin as to contact nerves located below the outer layers of the epidermis causing significant pain and discomfort, but are long enough to cooperate with each other to provide sufficient adhesion to the skin.
- Elements 14 can be sized to extend into the portion of skin lying below the stratum corneum layer of the skin because of the small size of elements 14 and the spacing between nerves at this depth.
- plastic elements 14 may have a length (height of the plastic elements 14 ), L, of about 0.10 mm.
- the length of elements 14 can be selected for the particular use.
- cone 18 tapers from a larger diameter proximal base 22 to a distal pointed tip 24 .
- the tip may have an angle of about 10° to 35°, for example about 20°.
- the conical shape and sharp point of elements 14 ease their penetration into epidermis 16 .
- the diameter of base 22 is selected to be large enough to help prevent breaking off of the projecting elements 14 from backing 12 , while limiting the size of the opening made in the outer surface 16 a of epidermis 16 .
- cone 18 may have a base diameter, D, of about 0.06 mm (0.002′′) to 0.4 mm (0.016′′), e.g., about 0.1 mm (0.004′′).
- Backing 12 may have a thickness, T, of about 0.08 mm to about 0.2 mm (0.003′′ to 0.008′′) to provide member 10 with sufficient handling characteristics.
- the skin-penetrating projecting plastic elements 14 can be other than conical in shape.
- elements 14 can be in the shape of a pyramid, a tetrahedron, or may be elliptical or square in cross-section, tapering to points at their distal ends. Rather than taper distally, elements 14 can progressively step down in diameter. Regardless of the particular shape selected, the elements 14 include sharp pointed tips 24 to ease tissue penetration.
- projecting elements 14 are shown with two discrete barbs 20 a, 20 b for retaining the elements 14 in the skin, though fewer or more barbs can be disposed on cone 28 to provide the desired retention characteristics.
- the location of barbs 20 can be selected to take advantage of the greater elasticity of the skin portions lying below the stratum corneum to provide greater holding force.
- barb 20 a has a top surface 23 a located a distance, d 1 , of about 0.13 mm (0.005′′) to 0.25 mm (0.01′′), for example about 0.2 mm (0.008′′) from base 22
- barb 20 b has a top surface 23 b located a distance, d 2 , of about 0.18 mm (0.007′′) to 0.3 mm (0.012′′), for example about 0.24 mm (0.0095′′) from base 22 .
- barbs 20 a, 20 b are roughly half-pyramids, each having a flat upper surface 23 a which is perpendicular to a longitudinal axis, A, of the projecting element 14 , and sloped sides 28 a, 28 b.
- Barbs 20 a, 20 b have a length, l, of about 0.0013 mm (0.00005′′) to 0.025 mm (0.001′′), for example about 0.0025 mm (0.0001′′), and a thickness, t ( FIG.
- member 10 In use, due to the elasticity of the skin, member 10 is secured to skin surface 16 a by surrounding of the barbs by the epidermis. To improve retention of member 10 to the skin, the barbs can be angled as shown in FIG. 5 . Here, a barb 20 c has a sloped upper surface 23 c.
- the density of projecting elements 14 on backing 12 depends on use. For example, in high strain applications, a higher density provides better skin attachment, whereas, in applications in which member 10 is not subjected to high strain, a lower density is better for limiting the possibility of inflammation. If the density is too high, it can require too much force for elements 14 to penetrate into the skin.
- a density of about 10 to 40 projecting elements in 0.1 in 2 area, for example about 25 projecting elements in 0.1 in 2 area provides good skin attachment while not requiring excessive insertion force.
- the projecting elements 14 are preferably spaced apart a distance, d ( FIG. 1 ), of about 1 mm (0.040′′) to 2.5 mm (0.1′′), for example about 1.6 mm (0.063′′).
- Skin attachment member 10 and its projecting elements 14 are preferably formed from a thermoplastic, biocompatible polymer, which is stiff enough to penetrate skin but not brittle, and capable of filling a mold and retaining its molded form.
- suitable polymers include nylon, polyethylene teraphthalate, and polyester.
- bacteria killing agents such as silver and/or copper and/or other bactericidal agents, or medication, such as an antibiotic, can be incorporated in the polymer from which member 10 is formed and/or a foam or gel 62 as shown in FIGS. 6A and 6B and discussed below.
- FIGS. 3C and 3D show projecting elements 14 for use in drug delivery which include longitudinal grooves 30 in an outer surface 32 of cone 18 . Although one or more grooves can be used, in this implementation four grooves 30 are shown, which provide passages for drug delivery as will be discussed in further detail below.
- skin attachment member 10 includes a foam or gel 62 in which the drug is placed, attached to upper lace 13 .
- the foam or gel provides a reservoir for the drug allowing the drug to be released over time.
- the description that follows describes some implementations that include a foam, however in other implementations a gel can be used instead of the foam.
- the gel can be for example a soft-gel such as gelatin, sol-gel, aerogel, and hydrogel.
- the skin attachment member 10 includes the projecting elements 14 and the sheet form base 12 having an upper face 13 and a lower face 11 .
- the projecting elements 14 extend from the upper face 13 of the sheet-form base 12 , as discussed above.
- Attached (e.g., physically bonded) to the upper lace 13 of the sheet form base 12 is the foam 62 .
- the projecting elements 14 and foam 62 can cover substantially the entire upper face 13 of the sheet form base 12 , allowing for varying sixes of skin attachment members.
- the foam 62 substantially covers the upper face 13 of the sheet-form base 12 , but the elements 14 do not substantially cover the upper face 13 of the sheet-form base 12 .
- the foam can be of varying heights with the foam in areas that do not have elements 14 being higher than the foam that surrounds the elements 14 .
- the foam can have a substantially uniform height, e.g., as shown in FIG. 7B .
- the foam 62 covers all of the upper face 13 of the sheet-form base 12 except for a perimeter area covered by an electrode 710 , which can be used to supply an electric current that further enhances drug penetration, as will be discussed in further detail below.
- the foam springs hack to a thickness that is greater than the height of the fastener elements, causing the fastener elements to be entirely submerged in the foam when the foam is not compressed (see, e.g., FIG. 8 ).
- FIG. 8 illustrates a skin attachment member 10 in which the height of the foam 62 is greater than the height of the elements 14 .
- the projecting elements 14 can push through the foam 62 and engage the epidermis 16 , as discussed above.
- foam 62 also protects element 14 until skin attachment takes place, helping to prevent damage, breakage or contamination of the elements 14 during handling prior to use.
- a skin or film can be applied to the exposed surface of foam 62 , or formed on the foam during the manufacture of the foam, forming a seal which can be punctured by elements 14 upon application to the skin, allowing a drug permeating the foam to pass through.
- FIG. 9 illustrates one method and apparatus for producing the above described skin attachment member.
- the method utilizes the continuous extrusion/roll-forming method for molding fastener elements on an integral, sheet-form base described in detail in U.S. Pat. No. 4,794,028, the disclosure of which is incorporated herein by reference.
- skin attachment member 10 is formed by an extrusion apparatus 900 including a molding/calendaring assembly 936 .
- the assembly includes an extrusion head 938 , a base roll 940 a, and a mold roll 940 b.
- the relative position and size of the rolls and other components is not to scale.
- the extrusion head 938 supplies a continuous sheet of molten resin 942 to a nip 944 formed between a base roll 940 a and a mold roll 940 b.
- a sheet of foam 946 is fed through the nip 944 between the mold roll 940 b and the molten resin 942 .
- Due to pressure applied at the nip by rolls 940 a and 940 b, molten resin 942 is forced through the foam 946 into projecting-element forming cavities 948 , forming the elements 14 .
- a guide roller 950 is situated diagonally upwardly to assist in the removal of the finished touch fastener 100 from mold roll 940 b.
- a set of upper and lower take-up rollers 952 , 954 are situated forwardly of the guide roller 950 . Downstream from the take-up rollers is a winder for winding continuous strip 10 ′ on spool 964 for subsequent, shipment, storage and use.
- FIG. 10 shows an alternative process for manufacturing a touch fastener having a foam embedded into the upper face of a sheet-form base.
- An injection die 1030 has an upper half arcuate surface 1032 that is substantially equal in curvature to a die wheel 1034 , and a lower half surface 1036 having a curvature that defines a predetermined gap with respect to the curved surface of the die wheel 1034 .
- the injection die 1030 has a resin extrusion outlet 1038 , which is situated centrally of the upper and lower surfaces 1032 , 1036 and from which molten resin 1040 is extruded in a sheet form under a predetermined pressure.
- a sheet of foam 1046 is drawn from a roll and introduced between the upper arcuate surface 1032 of the injection die 1030 and the circumferential surface of the die wheel 1034 .
- a guide roller 1050 is situated diagonally upwardly, and a set of upper and lower take-up rollers 1052 , 1054 rotating at a speed slightly higher than the rotating speed of the die wheel 1034 , are situated forwardly of the guide roller 1050 .
- the foam is compressed as it enters into the nip (as shown in FIG. 9 ) or the predetermined gap (as shown in FIG. 10 ), and is in a compressed state as the pressure forces the molten resin through the foam and into the hook cavities in the mold roll ( FIG. 9 ) or the die wheel ( FIG. 10 ). While foam generally springs back to its former thickness, a portion of the foam sticks (e.g., physically adheres or bonds) to the molten resin as it moves through the nip, and does not spring back to its original thickness. Thus, where the foam is embedded in the sheet form base, it generally has a thickness that is less than its thickness prior to adhering to the molten resin.
- the portions of the foam in direct contact with the fastener elements also physically bond to the molten resin that enters into the mold cavity ( 948 or 1048 ), causing an even greater reduction in the springing back of the foam in areas of the sheet form base adjacent to fastener elements.
- the degree to which a foam springs back to it original thickness varies with the type and density of foam and is generally expressed as a percentage.
- mold roller 940 b (die wheel 1034 has a similar structure) is substantially identical with the structure disclosed in U.S. Pat. No. 4,775,310, entitled APPARATUS FOR MAKING A SEPARATE FASTENER, which is incorporated herein by reference in its entirety.
- Mold roller 940 b defines a multiplicity of projecting-element-forming cavities 948 with their bases opening to the circumferential surface of the die wheel. The mold roller 940 b is driven to rotate in the direction indicated by the arrow in FIG. 9 .
- Roller 940 b (die wheel 1034 ) is a cooled mold roll having a set of stacked parallel plates 1120 ( FIG. 11B ) in which edge formations 1130 define rows of projecting element-mold cavities 948 .
- Roller 940 a is a pressure roll which coacts with mold roll 940 b for formation of continuous strip 10 .
- mold roll 940 b includes a series of stacked plates 1120 having edge formations 1130 on either side of each plate. When stacked, plates 1120 together define projecting element-forming cavities 948 within which projecting elements 14 are formed. Plates 1120 also define water passages 1140 for cooling of continuous strip 10 .
- plates 1120 of mold roll 940 b can be formed by etching a cone shape 1150 for a length of about 0.004′′ from roll edge.
- the remaining tip portion 1110 of the cone is formed by laser machining ( FIG. 11E ) in which a laser 1160 , under computer position control, is used to remove material from the plate to form the tip portion.
- Barb impressions 20 a ′ and 20 b ′ can also be formed using laser machining.
- the laser can also be controlled to form grooves 30 in cone 18 (shown in FIGS. 3A and C).
- the mold rolls are preferably formed of beryllium copper, the temperature of which is controlled during molding such that the resin does not cool too fast during application.
- FIG. 12 shows an alternative embodiment of a mold cavity in which a first plate 1120 defines an edge formation 1130 as described above, and a second plate 1120 ′ defines an edge formation 1130 ′ having a tip 1170 terminating prior to a tip 1180 of edge formation 1130 .
- distal tip 24 of element 12 is defined by tip 1180 .
- Suitable processes for making the skin attachment member and for attaching the skin attachment member to a foam are described in U.S. patent application Ser. No. 09/440,384, entitled SKIN ATTACHMENT MEMBER, the entire disclosure of which is hereby incorporated by reference, and further described in U.S. patent application No. 10/997,748, entitled MOLDED TOUCH FASTENERS AND METHODS OF MANUFACTURE, the entire disclosure of which is hereby incorporated by reference.
- the mold roils can be arranged such that the rows of elements 14 are offset or otherwise distributed on backing 12 .
- the elements 14 can be arranged such that they are completely or partially covered by foam 62 . Additionally, the elements 14 can be formed in groups such that there are areas of foam on skin attachment member 10 with and without the projecting elements 14 .
- the foam without projecting elements 14 can surround an area having both projecting elements 14 and foam.
- the projecting elements 14 can also be formed such that their longitudinal axes are not perpendicular to backing 12 or are distributed at various angles to hacking 12 . While enough of the projecting elements 14 should include barbs 20 to provide the desired degree of securement to the skin, not all of projecting elements 14 need include barbs 20 .
- the foam 62 of the skin attachment member is made from a material that is permeable to a selected drug and allows the drug to be delivered at a controlled rate.
- the foam material can be made from biocompatible polymers, copolymers, silicone rubbers, or any other material having the correct properties to allow for controlled drug delivery. The selection of the foam material will depend upon the physical properties of the foam material and their interaction with the particular drug to be administered. Examples of materials that can be used are polyolefin, polyvinyl chloride, poly (ethylene), poly (vinyl alcohol), poly (urethanes), poly (siloxanes), acrylic, polyisobutylene, polydimethylsiloxane, and polyether
- the skin attachment members 10 described above can be made in a continuous sheet form and cut into any shape.
- the skin attachment members 10 can be die-cut. Suitable processes for cutting a skin attachment member into a shape by die cutting are described, e.g., in U.S. Pat. No. 5,286,431, to Banfield et al., entitled MOLDED PRODUCT HAVING INSERT MOLD-IN FASTENER, the entire disclosure of which is herein incorporated by reference, and are further described in U.S. Pat. No.
- a drug or a drug and a penetration enhancer is applied to the foam before application to a person's skin. Suitable penetration enhancers are discussed below.
- the drug can be sprayed onto the loam (for a liquid), spread over the foam (for a paste, cream, or a gel), or soaked into the foam (for a liquid, cream, or a gel).
- transdermal administration of drugs has been limited to drugs having a molecular weight of less than about 500 Daltons and having the proper degree of lipophilicity, and having a melting point of less than 200° C.
- larger molecular weight molecules can be administered transdermally.
- the skin consists of two main layers: the epidermis 16 and the dermis 1330 . These layers contain, among other things, blood vessels that allow the drugs to be absorbed into the circulation and nerves.
- the main barrier to permeability of a drug is a layer of the epidermis called the stratum corneum 1310 .
- the stratum corneum seen greatly magnified in 13 B, is composed of several layers of flattened, dead keratinocytes (horny cells) 1350 connected by desmosomes and embedded in a lipid matrix 1340 forming a “brick and mortar” type of barrier to drug penetration.
- drugs pass through the stratum corneum's “brick and mortar” barrier by two main routes consisting of the transcellular route 1365 , where the drugs have to pass through multiple layers of dead keratinocytes and lipid, and the intercellular route 1360 , where drugs pass through the lipid layers between the cells.
- the skin is relatively impermeable to molecules having a molecular weight of greater than 500 Daltons, and to molecules which do not have the proper solubility in both water and lipid unless a process other than permeability of the drug is used to breach this barrier.
- FIG. 13C shows the skin attachment member 10 with elements 14 penetrating into the epidermis 16 and foam 62 containing the desired drug in contact with the outer surface of the epidermis 16 a.
- Elements 14 having grooves 30 ( FIG. 3C ), form passages through the “brick and mortar” barrier of the stratum corneum by penetrating through the stratum corneum.
- the passages created by the elements 14 allow both smaller and larger molecular weight molecules to pass through the barrier increasing the rate of absorption for both, while at the same time not causing pain because they do not penetrate into the dermis 1330 where the nerves are located.
- Skin penetration can be further enhanced by combining a chemical penetration enhancer with the drug.
- Chemical enhancers improve the transport of the drug across the “brick and mortar” barrier of the epidermal layer.
- penetration enhancers are alcohols (such as methanol and ethanol), DMSO, and DMF.
- DMSO in concentrations as low as 2 percent, will improve topical absorption of drugs without creating the taste and smell associated with higher concentrations of the chemical.
- the penetration enhancer By adding the penetration enhancer to the drug incorporated into foam 62 of skin attachment member 10 , the drug's permeability through the stratum corneum 1310 is increased.
- the time period for which skin attachment member 10 is applied to the skin, allowing the drug to permeate out of the foam and through the skin, is determined by the physical properties of the drug and the foam. Depending on the respective physical properties, the skin attachment member 10 may stay attached from a period of several minutes to several days. Typical examples of the time period that the drug can be applied to the skin include 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 2 days, etc. As long as there is drug available in the foam for delivery through the skin at a rate appropriate to achieve the desired clinical response, the skin attachment member may remain attached to the skin.
- the duration for which the skin attachment member is applied can be extended by incorporating a timed release formulation of the drug into the foam or by using foam with the appropriate timed release characteristics. This allows the drug to be delivered over an extended, time period with less frequent need to replace the skin attachment member as the drug is depleted. Other methods for timed release of the drug include microencapsulation.
- drug delivery is controlled by using an electric current to drive the drug through the skin barrier.
- This process can be continuous or can be intermittent (or continuous with an intermittent bolus) on a predetermined time schedule and/or controlled by a sensor which determines when the drug needs to be given.
- FIG. 13D shows the skin attachment member 10 of FIG. 8 attached to the surface of the epidermis 16 a, so that electrode 710 contacts the skin.
- a voltage V 1 is applied between electrode 710 and electrode 1375 positioned on another area of the skin surface.
- electrode 710 acts as an anode and causes the positively charge molecule 1380 to flow away from the electrode and out of the foam through the skin barrier into the dermis where the drug can be absorbed into the circulation.
- the voltage is reversed causing the negatively charged molecules to migrate away from the electrode 710 through the skin barrier.
- a sensor (not shown) monitors a parameter, such as blood glucose level, and activates the circuit applying the appropriate voltage to electrode 710 when the parameter dictates that the drug needs to be delivered. In this manner, there can be a continuous delivery of drug at a lower rate of permeability, and then an enhanced delivery of the drug when the sensor activates the electrode.
- the permeation of the drug through the skin can be modified by the combination of skin penetration elements 14 , and/or the penetration enhancer, and/or the electric current applied by means of the electrode 710 .
- a resistive element capable of producing heat in response to a current, can be applied to the skin attachment member 10 (instead of electrode 710 ), and a current can be generated through the resistive element by applying voltage V 1 across the resistive element.
- the resistive element produces a local heating effect causing the drug to permeate through the skin more readily.
- the resistive element can be applied either peripherally around the foam as is shown for the electrode 710 , or to the lower face 11 (or in any other location on skin attachment member 10 that produces a local heating effect), allowing the heat to pass through the skin attachment member 10 and heat the drug, foam and skin underneath, causing increased skin permeability.
- different patterns of elements 14 can be formed on sheet form base 12 , as well as different heights and/or distribution of foam 62 on sheet form base 12 .
- the distribution and relationship of the foam 62 to the elements 14 can vary depending on the application.
- the elements can be sized and/or shaped differently as discussed above, and/or have a different number and/or shape of the barbs 20 .
- Different types of foam can be attached to the sheet form base and different types of medications can be used for application by the skin attachment member 10 , as well as different types of penetration enhancers.
- a sheet form base 12 having an upper face 13 and a lower face 11 and elements 14 positioned on the upper face 13 , is positioned on a base roll.
- a foam material 62 having openings (e.g., slits or holes) is positioned on a material roll. Pressure is applied to the sheet form base and foam material at the nip of the base roll and material roll while the sheet form base 12 and the foam material 62 are pulled simultaneously from the base roll and material roll. The pressure causes the male fastener elements 14 of the sheet form base 12 to engage the foam material 62 in the portions of the foam having holes.
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Abstract
Description
- This application relates to skin penetrating touch fasteners.
- Transdermal delivery of drugs (medications) has been around for a number of years. Transdermal delivery of drugs offers many advantages over more traditional routes of medicating a patient, i.e. oral administration of the medication or injection methods. One of the advantages of transdermal administration is that it avoids the negative side effects of oral administration, for example irritation of the gastrointestinal tract (some medicines cause ulcers and gastrointestinal bleeding). Transdermal administration also avoids hepatic and systemic toxicity that can result from the necessarily larger doses of the drag that have to be administered orally in order to compensate for hepatic first pass metabolism of drugs absorbed through the gastrointestinal tract, and to maintain therapeutic blood levels of the drug over the dosing interval. Moreover, transdermal delivery offers a painless, convenient, and non-invasive way to administer drugs, providing more stable blood levels with less frequent dosing because of controlled release of the medication. Unfortunately, without altering the skin's barrier these benefits can only be achieved for a few drugs that are able to cross the barrier established by the skin, such as some cardiac drugs and hormones.
- The stratum corneum (composed of a lipid bilayers located between dead keratinocytes cells) provides the main resistance to drug delivery through the skin, limiting the transdermal route to drugs having a low molecular weight, i.e. less than 500 Daltons, and having the appropriate lipophilicity. Typically, drugs suitable for transdermal delivery are non-ionic, and/or have high potency, such that therapeutic effects can be achieved with small amounts of transdermal absorption. Other factors affecting absorption are the site of application, length of application, the addition of an absorption vehicle (penetration enhancer or enhancers), such as organic solvents like dimethyl sulfoxide (DMSO), and the integrity of the epidermal barrier. Transdermal deliver of drugs having a molecular weight of greater than 500 Daltons requires some type of skin permeation enhancement mechanism, such as chemical penetration enhancers. Therefore, transdermal administration of drugs has generally been limited to drugs having the required physiochemical properties allowing absorption through the epidermal layer.
- Improvements in the transdermal delivery of drugs are sought, such as improvements that may lead to the applicability of transdermal delivery of drags to a broad group of medicines and higher molecular weight biomolecules.
- In one aspect the disclosure features a skin attachment member, which has a backing with a first surface and a second surface. A plurality of skin penetrating elements extend integrally from the first surface of the backing to a distal tip. The skin penetrating elements are sized to avoid contact with the nerves below the epidermal skin layer. The skin attachment member has a foam disposed on the first surface of the backing, such that at least a portion of the foam is disposed between at least some of the skin penetrating elements.
- Some implementations may include one or more of the following features. The foam may be, for example, polyvinyl chloride (PVC) or polyurethane (PU). A pharmaceutical composition is disposed within the foam. The pharmaceutical composition may be in the form, for example, of a cream, a gel, or a liquid. In other implementations, the pharmaceutical composition is a biomolecule. The biomolecule can be a hormone or an antibody. In some implementations, the pharmaceutical composition is a small molecule. The pharmaceutical composition can be a controlled release formulation. The pharmaceutical composition can further include a vehicle. In some implementations, a penetration enhancer is disposed within the foam. An adhesive can be disposed on a surface of the foam. In some implementations, at least a portion of the foam extends to a height greater than the height of at least some of the skin penetration elements. In this and other implementations, a plurality of the skin penetrating elements may extend to a height greater than the foam.
- In some implementations, a plurality of the skin penetrating elements have a groove extending lengthwise from the base towards the distal tip. e.g., from the base to the tip. Some of the skin penetrating elements have at least one retention barb extending from an outer side surface of the skin penetrating element. The base of the skin penetrating elements is a plastic resin. The skin penetrating elements have a height of about 0.004 to about 0.040 inches, for example, about 0.012 inches. In another aspect, the disclosure features a skin attachment member having a backing, which has a first surface and a second surface. A plurality of skin penetrating elements extend integrally from the first surface of the backing to a distal tip, and a foam is disposed on the first surface of the backing, such that at least a portion of the foam is disposed between at least some of the skin penetrating elements, the foam having a pharmaceutical composition disposed therein.
- In another aspect, the disclosure features a method of delivering a pharmaceutical composition by attaching a skin attachment member to the skin of a subject, and maintaining the skin attachment member on the skin of the subject for a time sufficient to allow at least a portion of a pharmaceutical composition to permeate the epidermis of the subject. The skin attachment member has a backing, which has a first surface and a second surface, and a plurality of skin penetrating elements extending integrally from the first surface of the backing to a distal tip. The skin penetrating elements are sized to avoid contact with nerves below the epidermal skin layer. A plurality of the skin penetrating elements include at least one retention barb extending from an outer side surface of the skin penetrating element. A foam is disposed on the first surface of the backing, such that a portion of the foam is disposed between at least some of the skin penetrating elements. The pharmaceutical composition is disposed within the foam.
- In some implementations, the method includes providing a skin penetrating enhancer. The skin penetrating enhancer is disposed within the foam. In other implementations, the method includes heating the skin attachment member. In some implementations, the method includes maintaining the skin attachment member on the subject for at least 2 hours, for at least 12 hours, for at least 24 hours, and for at least one week.
- The details of one or more implementations are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.
-
FIG. 1 is a highly magnified, side view of a section of a skin attachment member, shown secured in the epidermis; -
FIG. 2 is a diagrammatic perspective view of the section of the skin attachment member ofFIG. 1 ; -
FIG. 3A is a side view of the skin-penetrating element of the skin attachment member ofFIG. 1 : -
FIG. 3B is another side view of the element ofFIG. 3A , rotated 90 degrees relative toFIG. 3A ; -
FIG. 3C is an end view of the element ofFIG. 3A taken along lines 3C-3C inFIG. 3A ; -
FIG. 3D is a cross-sectional view of the element ofFIG. 3A taken alonglines 3D-3D inFIG. 3B ; -
FIG. 4 is a perspective view of section A ofFIG. 3B , showing a barb of the element ofFIG. 3A : -
FIG. 5 shows an alternative embodiment of a barb; -
FIG. 6A is a side view of a skin attachment member with foam attached to the upper face of a sheet form base; -
FIG. 6B is a perspective view of a skin attachment member ofFIG. 2A ; -
FIG. 7A is an end view of a skin attachment member having foam attached to the upper face of a sheet form base where foam extends longitudinally beyond an array of fastener elements on the upper face of the sheet form base; -
FIG. 7B is an end view of a skin attachment member having foam attached to the upper face of a sheet form base where foam extend longitudinally beyond an array of fastener elements on the tipper face of the sheet form base and having electrical elements on one or more peripheral edges; -
FIG. 8 is a cross-sectional view of a skin attachment member having foam attached to the upper face of a sheet form base, in which the height of the foam is greater than the height of the elements; -
FIG. 9 shows schematically an apparatus and process for manufacturing a skin attachment member having foam attached to the upper face of a sheet form base; -
FIG. 10 shows schematically an apparatus and process for manufacturing a skin attachment member having foam attached to the upper face of a sheet form base; -
FIG. 11A is a side view of the mold roll ofFIG. 9 ; -
FIG. 11B is a cross-sectional view of a portion of the mold roll, taken alonglines 11B-11B inFIG. 11A ; -
FIG. 11C is an end view of the mold roll, taken along lines 11C-11C inFIG. 11B ; -
FIG. 11D is a magnified side view ofportion 11D of the mold roll ofFIG. 11A ; -
FIG. 11E shows laser machining of the mold roll; -
FIG. 12 shows art alterative edge formation on a mold roll; -
FIG. 13A shows the different layers of a segment of skin; -
FIG. 13B is a enlarged view of the section 13B shown inFIG. 13A ; -
FIG. 13C shows a highly magnified view of the skin attachment member with foam attached secured to the epidermis; and -
FIG. 13D shows a highly magnified view of the skin attachment member and attached foam with a strip of conductive material attached to a non-foam covered peripheral edge of the upper face. - Referring to
FIGS. 1 and 2 , askin attachment member 10, formed of plastic resin, includes abacking 12 having anupper face 13 and alower face 11, and multiple, parallel rows of integrally molded, pointed projections orelements 14 extending from backing 12 for penetrating into theepidermis 16. Although the pattern has been described as multiple, parallel rows ofelements 14, different patterns of elements molded onto backing 12 can be used. The skin-penetratingelements 14 each, include a cone-shapedbody 18 with one or morediscrete barbs 20 extending from the body for securingskin attachment member 10 toepidermis 16. - The length of
elements 14 is selected such that the elements do not penetrate so far into the skin as to contact nerves located below the outer layers of the epidermis causing significant pain and discomfort, but are long enough to cooperate with each other to provide sufficient adhesion to the skin.Elements 14 can be sized to extend into the portion of skin lying below the stratum corneum layer of the skin because of the small size ofelements 14 and the spacing between nerves at this depth. For example, referring also toFIG. 3A ,plastic elements 14 may have a length (height of the plastic elements 14), L, of about 0.10 mm. (0.004″) to 1.0 mm (0.04″), or preferably of about 0.20 mm (0.008″) to 0.41 mm (0.016″), e.g., about 0.3 mm (0.012″). Since the thickness of the epidermis varies, for example, with age, the location on skin, and the gender of the patient, the length ofelements 14 can be selected for the particular use. - Referring, to
FIGS. 3A and 3B ,cone 18 tapers from a larger diameterproximal base 22 to a distalpointed tip 24. The tip may have an angle of about 10° to 35°, for example about 20°. The conical shape and sharp point ofelements 14 ease their penetration intoepidermis 16. The diameter ofbase 22 is selected to be large enough to help prevent breaking off of the projectingelements 14 from backing 12, while limiting the size of the opening made in theouter surface 16 a ofepidermis 16. For example,cone 18 may have a base diameter, D, of about 0.06 mm (0.002″) to 0.4 mm (0.016″), e.g., about 0.1 mm (0.004″).Backing 12 may have a thickness, T, of about 0.08 mm to about 0.2 mm (0.003″ to 0.008″) to providemember 10 with sufficient handling characteristics. - The skin-penetrating projecting
plastic elements 14 can be other than conical in shape. For example,elements 14 can be in the shape of a pyramid, a tetrahedron, or may be elliptical or square in cross-section, tapering to points at their distal ends. Rather than taper distally,elements 14 can progressively step down in diameter. Regardless of the particular shape selected, theelements 14 include sharppointed tips 24 to ease tissue penetration. - Referring to
FIGS. 3A and 38 , projectingelements 14 are shown with twodiscrete barbs elements 14 in the skin, though fewer or more barbs can be disposed on cone 28 to provide the desired retention characteristics. The location ofbarbs 20 can be selected to take advantage of the greater elasticity of the skin portions lying below the stratum corneum to provide greater holding force. For example,barb 20 a has atop surface 23 a located a distance, d1, of about 0.13 mm (0.005″) to 0.25 mm (0.01″), for example about 0.2 mm (0.008″) frombase 22, andbarb 20 b has atop surface 23 b located a distance, d2, of about 0.18 mm (0.007″) to 0.3 mm (0.012″), for example about 0.24 mm (0.0095″) frombase 22. - Referring to
FIG. 4 , which is an enlarged view of section A ofFIG. 3B ,barbs upper surface 23 a which is perpendicular to a longitudinal axis, A, of the projectingelement 14, and slopedsides 28 a, 28 b.Barbs FIG. 3 d), of about 0.0013 mm (0.00005″) to 0.025 mm (0.001″), for example about 0.0025 mm (0.0001″), which tapers to apoint 26 at an angle, α, of about 70° to 120°, for example about 90°. - In use, due to the elasticity of the skin,
member 10 is secured toskin surface 16 a by surrounding of the barbs by the epidermis. To improve retention ofmember 10 to the skin, the barbs can be angled as shown inFIG. 5 . Here, abarb 20 c has a slopedupper surface 23 c. - The density of projecting
elements 14 on backing 12 depends on use. For example, in high strain applications, a higher density provides better skin attachment, whereas, in applications in whichmember 10 is not subjected to high strain, a lower density is better for limiting the possibility of inflammation. If the density is too high, it can require too much force forelements 14 to penetrate into the skin. A density of about 10 to 40 projecting elements in 0.1 in2 area, for example about 25 projecting elements in 0.1 in2 area provides good skin attachment while not requiring excessive insertion force. In this case the projectingelements 14 are preferably spaced apart a distance, d (FIG. 1 ), of about 1 mm (0.040″) to 2.5 mm (0.1″), for example about 1.6 mm (0.063″). -
Skin attachment member 10 and its projectingelements 14 are preferably formed from a thermoplastic, biocompatible polymer, which is stiff enough to penetrate skin but not brittle, and capable of filling a mold and retaining its molded form. Example of suitable polymers include nylon, polyethylene teraphthalate, and polyester. Also, bacteria killing agents, such as silver and/or copper and/or other bactericidal agents, or medication, such as an antibiotic, can be incorporated in the polymer from whichmember 10 is formed and/or a foam orgel 62 as shown inFIGS. 6A and 6B and discussed below. -
FIGS. 3C and 3D show projecting elements 14 for use in drug delivery which includelongitudinal grooves 30 in anouter surface 32 ofcone 18. Although one or more grooves can be used, in this implementation fourgrooves 30 are shown, which provide passages for drug delivery as will be discussed in further detail below. - Referring to
FIGS. 6A and 6B , to facilitate transdermal delivery,skin attachment member 10 includes a foam orgel 62 in which the drug is placed, attached toupper lace 13. The foam or gel provides a reservoir for the drug allowing the drug to be released over time. The description that follows describes some implementations that include a foam, however in other implementations a gel can be used instead of the foam. The gel can be for example a soft-gel such as gelatin, sol-gel, aerogel, and hydrogel. - Referring again to
FIG. 6A , theskin attachment member 10 includes the projectingelements 14 and thesheet form base 12 having anupper face 13 and alower face 11. The projectingelements 14 extend from theupper face 13 of the sheet-form base 12, as discussed above. Attached (e.g., physically bonded) to theupper lace 13 of thesheet form base 12 is thefoam 62. As depicted inFIG. 6B , the projectingelements 14 andfoam 62 can cover substantially the entireupper face 13 of thesheet form base 12, allowing for varying sixes of skin attachment members. - In some implementations, e.g., as shown in
FIG. 7A , thefoam 62 substantially covers theupper face 13 of the sheet-form base 12, but theelements 14 do not substantially cover theupper face 13 of the sheet-form base 12. As shown inFIG. 7A , the foam can be of varying heights with the foam in areas that do not haveelements 14 being higher than the foam that surrounds theelements 14. - In other implementations, the foam can have a substantially uniform height, e.g., as shown in
FIG. 7B . InFIG. 7B , thefoam 62 covers all of theupper face 13 of the sheet-form base 12 except for a perimeter area covered by anelectrode 710, which can be used to supply an electric current that further enhances drug penetration, as will be discussed in further detail below. - In some implementations, the foam springs hack to a thickness that is greater than the height of the fastener elements, causing the fastener elements to be entirely submerged in the foam when the foam is not compressed (see, e.g.,
FIG. 8 ).FIG. 8 illustrates askin attachment member 10 in which the height of thefoam 62 is greater than the height of theelements 14. Although the projectingelements 14 are entirely submerged in thefoam 62, the projectingelements 14 can push through thefoam 62 and engage theepidermis 16, as discussed above. Thus,foam 62 also protectselement 14 until skin attachment takes place, helping to prevent damage, breakage or contamination of theelements 14 during handling prior to use. In some implementations, a skin or film can be applied to the exposed surface offoam 62, or formed on the foam during the manufacture of the foam, forming a seal which can be punctured byelements 14 upon application to the skin, allowing a drug permeating the foam to pass through. -
FIG. 9 illustrates one method and apparatus for producing the above described skin attachment member. The method utilizes the continuous extrusion/roll-forming method for molding fastener elements on an integral, sheet-form base described in detail in U.S. Pat. No. 4,794,028, the disclosure of which is incorporated herein by reference. As shown inFIG. 9 ,skin attachment member 10 is formed by anextrusion apparatus 900 including a molding/calendaring assembly 936. The assembly includes anextrusion head 938, abase roll 940 a, and amold roll 940 b. InFIG. 9 , the relative position and size of the rolls and other components is not to scale. - The
extrusion head 938 supplies a continuous sheet ofmolten resin 942 to a nip 944 formed between abase roll 940 a and amold roll 940 b. Asmolten resin 942 enters nip 944, a sheet offoam 946 is fed through thenip 944 between themold roll 940 b and themolten resin 942. Due to pressure applied at the nip byrolls molten resin 942 is forced through thefoam 946 into projecting-element forming cavities 948, forming theelements 14. Aguide roller 950 is situated diagonally upwardly to assist in the removal of the finished touch fastener 100 frommold roll 940 b. A set of upper and lower take-uprollers guide roller 950. Downstream from the take-up rollers is a winder for windingcontinuous strip 10′ onspool 964 for subsequent, shipment, storage and use. -
FIG. 10 shows an alternative process for manufacturing a touch fastener having a foam embedded into the upper face of a sheet-form base. An injection die 1030 has an upper halfarcuate surface 1032 that is substantially equal in curvature to adie wheel 1034, and alower half surface 1036 having a curvature that defines a predetermined gap with respect to the curved surface of thedie wheel 1034. The injection die 1030 has aresin extrusion outlet 1038, which is situated centrally of the upper andlower surfaces molten resin 1040 is extruded in a sheet form under a predetermined pressure. - A sheet of
foam 1046 is drawn from a roll and introduced between the upperarcuate surface 1032 of the injection die 1030 and the circumferential surface of thedie wheel 1034. Aguide roller 1050 is situated diagonally upwardly, and a set of upper and lower take-uprollers die wheel 1034, are situated forwardly of theguide roller 1050. - The foam is compressed as it enters into the nip (as shown in
FIG. 9 ) or the predetermined gap (as shown inFIG. 10 ), and is in a compressed state as the pressure forces the molten resin through the foam and into the hook cavities in the mold roll (FIG. 9 ) or the die wheel (FIG. 10 ). While foam generally springs back to its former thickness, a portion of the foam sticks (e.g., physically adheres or bonds) to the molten resin as it moves through the nip, and does not spring back to its original thickness. Thus, where the foam is embedded in the sheet form base, it generally has a thickness that is less than its thickness prior to adhering to the molten resin. Moreover, the portions of the foam in direct contact with the fastener elements also physically bond to the molten resin that enters into the mold cavity (948 or 1048), causing an even greater reduction in the springing back of the foam in areas of the sheet form base adjacent to fastener elements. The degree to which a foam springs back to it original thickness varies with the type and density of foam and is generally expressed as a percentage. - The structure of the
mold roller 940 b (diewheel 1034 has a similar structure) is substantially identical with the structure disclosed in U.S. Pat. No. 4,775,310, entitled APPARATUS FOR MAKING A SEPARATE FASTENER, which is incorporated herein by reference in its entirety.Mold roller 940 b defines a multiplicity of projecting-element-formingcavities 948 with their bases opening to the circumferential surface of the die wheel. Themold roller 940 b is driven to rotate in the direction indicated by the arrow inFIG. 9 . -
Roller 940 b (die wheel 1034) is a cooled mold roll having a set of stacked parallel plates 1120 (FIG. 11B ) in whichedge formations 1130 define rows of projecting element-mold cavities 948.Roller 940 a is a pressure roll which coacts withmold roll 940 b for formation ofcontinuous strip 10. Referring toFIGS. 11A and 11B ,mold roll 940 b includes a series ofstacked plates 1120 havingedge formations 1130 on either side of each plate. When stacked,plates 1120 together define projecting element-formingcavities 948 within which projectingelements 14 are formed.Plates 1120 also definewater passages 1140 for cooling ofcontinuous strip 10. - Referring to
FIG. 11C and 11D , which is an enlarged view ofsections 11C and 11D ofFIGS. 11B and 11A respectively,plates 1120 ofmold roll 940 b can be formed by etching acone shape 1150 for a length of about 0.004″ from roll edge. The remaining tip portion 1110 of the cone is formed by laser machining (FIG. 11E ) in which alaser 1160, under computer position control, is used to remove material from the plate to form the tip portion.Barb impressions 20 a′ and 20 b′ can also be formed using laser machining. The laser can also be controlled to formgrooves 30 in cone 18 (shown inFIGS. 3A and C). The mold rolls are preferably formed of beryllium copper, the temperature of which is controlled during molding such that the resin does not cool too fast during application. -
FIG. 12 shows an alternative embodiment of a mold cavity in which afirst plate 1120 defines anedge formation 1130 as described above, and asecond plate 1120′ defines anedge formation 1130′ having atip 1170 terminating prior to atip 1180 ofedge formation 1130. Thus,distal tip 24 ofelement 12 is defined bytip 1180. Suitable processes for making the skin attachment member and for attaching the skin attachment member to a foam are described in U.S. patent application Ser. No. 09/440,384, entitled SKIN ATTACHMENT MEMBER, the entire disclosure of which is hereby incorporated by reference, and further described in U.S. patent application No. 10/997,748, entitled MOLDED TOUCH FASTENERS AND METHODS OF MANUFACTURE, the entire disclosure of which is hereby incorporated by reference. - While
skin attachment member 10 has been described as including multiple, parallel rows of projectingelements 14, the mold roils can be arranged such that the rows ofelements 14 are offset or otherwise distributed on backing 12. Theelements 14 can be arranged such that they are completely or partially covered byfoam 62. Additionally, theelements 14 can be formed in groups such that there are areas of foam onskin attachment member 10 with and without the projectingelements 14. The foam without projectingelements 14 can surround an area having both projectingelements 14 and foam. The projectingelements 14 can also be formed such that their longitudinal axes are not perpendicular to backing 12 or are distributed at various angles tohacking 12. While enough of the projectingelements 14 should includebarbs 20 to provide the desired degree of securement to the skin, not all of projectingelements 14 need includebarbs 20. - The
foam 62 of the skin attachment member is made from a material that is permeable to a selected drug and allows the drug to be delivered at a controlled rate. The foam material can be made from biocompatible polymers, copolymers, silicone rubbers, or any other material having the correct properties to allow for controlled drug delivery. The selection of the foam material will depend upon the physical properties of the foam material and their interaction with the particular drug to be administered. Examples of materials that can be used are polyolefin, polyvinyl chloride, poly (ethylene), poly (vinyl alcohol), poly (urethanes), poly (siloxanes), acrylic, polyisobutylene, polydimethylsiloxane, and polyether - The
skin attachment members 10 described above can be made in a continuous sheet form and cut into any shape. For example, theskin attachment members 10 can be die-cut. Suitable processes for cutting a skin attachment member into a shape by die cutting are described, e.g., in U.S. Pat. No. 5,286,431, to Banfield et al., entitled MOLDED PRODUCT HAVING INSERT MOLD-IN FASTENER, the entire disclosure of which is herein incorporated by reference, and are further described in U.S. Pat. No. 5,766,385, to Pollard et al., entitled SEPARABLE FASTENER HAVING DIE-CUT PROTECTIVE COVER WITH PULL TAB AND METHOD OF MAKING SAME, the entire disclosure of which is incorporated herein by reference. - Alter making and cutting the skin attachment member to the desired shape, a drug or a drug and a penetration enhancer is applied to the foam before application to a person's skin. Suitable penetration enhancers are discussed below. Depending on the consistency of the drug (or drug/enhancer combination), the drug can be sprayed onto the loam (for a liquid), spread over the foam (for a paste, cream, or a gel), or soaked into the foam (for a liquid, cream, or a gel). Typically, transdermal administration of drugs has been limited to drugs having a molecular weight of less than about 500 Daltons and having the proper degree of lipophilicity, and having a melting point of less than 200° C. However, through the use of projecting
elements 14, which create a passage through the epidermal layer, larger molecular weight molecules can be administered transdermally. The following are some (but not all) examples of the drugs that can be administered transdermally using the skin attachment member described herein: nitroglycerin, scopolamine, nicotine, clonidine, and fentanyl, estradiol, tulobuterol, testosterone, alprostadil, buprenorphine, dexamethasone, dextroamphetamine, androgen/estradiol, estradiol/progestin, testosterone/estradiol, flurbiprofen, lidocaine, albuterol, enalapril, dronabinol, ketorolac, alprazolam, cytarabine, atenolol, buprenorphine, isosorbide dinitrate, and prazosin also larger molecular weight molecules like glucagon-like peptide-1, parathyroid hormone, insulin, calcitonin, vaccines, RNAi, antibodies, and other biomolecules and macromolecules can be delivered transdermally. - In order to deliver drugs transdermally, the drugs must pass through the skin's natural barriers. Referring to
FIG. 13A , the skin consists of two main layers: theepidermis 16 and thedermis 1330. These layers contain, among other things, blood vessels that allow the drugs to be absorbed into the circulation and nerves. The main barrier to permeability of a drug is a layer of the epidermis called thestratum corneum 1310. The stratum corneum, seen greatly magnified in 13B, is composed of several layers of flattened, dead keratinocytes (horny cells) 1350 connected by desmosomes and embedded in alipid matrix 1340 forming a “brick and mortar” type of barrier to drug penetration. Typically, drugs pass through the stratum corneum's “brick and mortar” barrier by two main routes consisting of thetranscellular route 1365, where the drugs have to pass through multiple layers of dead keratinocytes and lipid, and theintercellular route 1360, where drugs pass through the lipid layers between the cells. Because of this “brick and mortar” type barrier the skin is relatively impermeable to molecules having a molecular weight of greater than 500 Daltons, and to molecules which do not have the proper solubility in both water and lipid unless a process other than permeability of the drug is used to breach this barrier. - In order to breach this barrier and make drugs more permeable through the skin, a person can apply
skin attachment member 10, having the desired drug permeated into the foam, to the outer surface of theskin 16 a causingelements 14 to penetrate into the epidermis.FIG. 13C shows theskin attachment member 10 withelements 14 penetrating into theepidermis 16 andfoam 62 containing the desired drug in contact with the outer surface of the epidermis 16 a.Elements 14, having grooves 30 (FIG. 3C ), form passages through the “brick and mortar” barrier of the stratum corneum by penetrating through the stratum corneum. Thus, the passages created by theelements 14 allow both smaller and larger molecular weight molecules to pass through the barrier increasing the rate of absorption for both, while at the same time not causing pain because they do not penetrate into thedermis 1330 where the nerves are located. - Skin penetration can be further enhanced by combining a chemical penetration enhancer with the drug. Chemical enhancers improve the transport of the drug across the “brick and mortar” barrier of the epidermal layer. A variety of enhancers exist, and they work by altering the structure of the skin lipids and/or enhancing the solubility of the diffusing drug. Some enhancers extract lipids from the stratum corneum, some disrupt the lipid matrix structure, some displace bound water, some loosen horny cells, some alter the skin partitioning coefficient, and some delaminate the stratum corneum. Examples of penetration enhancers are alcohols (such as methanol and ethanol), DMSO, and DMF. DMSO, in concentrations as low as 2 percent, will improve topical absorption of drugs without creating the taste and smell associated with higher concentrations of the chemical. By adding the penetration enhancer to the drug incorporated into
foam 62 ofskin attachment member 10, the drug's permeability through thestratum corneum 1310 is increased. - The time period for which
skin attachment member 10 is applied to the skin, allowing the drug to permeate out of the foam and through the skin, is determined by the physical properties of the drug and the foam. Depending on the respective physical properties, theskin attachment member 10 may stay attached from a period of several minutes to several days. Typical examples of the time period that the drug can be applied to the skin include 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 2 days, etc. As long as there is drug available in the foam for delivery through the skin at a rate appropriate to achieve the desired clinical response, the skin attachment member may remain attached to the skin. The duration for which the skin attachment member is applied can be extended by incorporating a timed release formulation of the drug into the foam or by using foam with the appropriate timed release characteristics. This allows the drug to be delivered over an extended, time period with less frequent need to replace the skin attachment member as the drug is depleted. Other methods for timed release of the drug include microencapsulation. - In some implementations, drug delivery is controlled by using an electric current to drive the drug through the skin barrier. This process can be continuous or can be intermittent (or continuous with an intermittent bolus) on a predetermined time schedule and/or controlled by a sensor which determines when the drug needs to be given.
FIG. 13D shows theskin attachment member 10 ofFIG. 8 attached to the surface of the epidermis 16 a, so thatelectrode 710 contacts the skin. A voltage V1 is applied betweenelectrode 710 andelectrode 1375 positioned on another area of the skin surface. For a positively charged drug molecule 1380 (or drug molecule mixed with penetration enhancer),electrode 710 acts as an anode and causes the positively charge molecule 1380 to flow away from the electrode and out of the foam through the skin barrier into the dermis where the drug can be absorbed into the circulation. For negatively charged molecules, the voltage is reversed causing the negatively charged molecules to migrate away from theelectrode 710 through the skin barrier. In some implementations, a sensor (not shown) monitors a parameter, such as blood glucose level, and activates the circuit applying the appropriate voltage to electrode 710 when the parameter dictates that the drug needs to be delivered. In this manner, there can be a continuous delivery of drug at a lower rate of permeability, and then an enhanced delivery of the drug when the sensor activates the electrode. Thus, the permeation of the drug through the skin can be modified by the combination ofskin penetration elements 14, and/or the penetration enhancer, and/or the electric current applied by means of theelectrode 710. - Similarly, a resistive element (not shown), capable of producing heat in response to a current, can be applied to the skin attachment member 10 (instead of electrode 710), and a current can be generated through the resistive element by applying voltage V1 across the resistive element. In this manner, the resistive element produces a local heating effect causing the drug to permeate through the skin more readily. The resistive element can be applied either peripherally around the foam as is shown for the
electrode 710, or to the lower face 11 (or in any other location onskin attachment member 10 that produces a local heating effect), allowing the heat to pass through theskin attachment member 10 and heat the drug, foam and skin underneath, causing increased skin permeability. - A number of implementations of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention.
- For example, different patterns of
elements 14 can be formed onsheet form base 12, as well as different heights and/or distribution offoam 62 onsheet form base 12. The distribution and relationship of thefoam 62 to theelements 14 can vary depending on the application. The elements can be sized and/or shaped differently as discussed above, and/or have a different number and/or shape of thebarbs 20. Different types of foam can be attached to the sheet form base and different types of medications can be used for application by theskin attachment member 10, as well as different types of penetration enhancers. - In an alternate method of making the
skin attachment member 10 with the foam attached, asheet form base 12, having anupper face 13 and alower face 11 andelements 14 positioned on theupper face 13, is positioned on a base roll. Afoam material 62 having openings (e.g., slits or holes) is positioned on a material roll. Pressure is applied to the sheet form base and foam material at the nip of the base roll and material roll while thesheet form base 12 and thefoam material 62 are pulled simultaneously from the base roll and material roll. The pressure causes themale fastener elements 14 of thesheet form base 12 to engage thefoam material 62 in the portions of the foam having holes. - Accordingly, other embodiments are within the scope of the following claims.
Claims (31)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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US11/739,244 US8439861B2 (en) | 2007-04-24 | 2007-04-24 | Skin penetrating touch fasteners |
PCT/US2008/060319 WO2008134237A1 (en) | 2007-04-24 | 2008-04-15 | Skin penetrating touch fasteners |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11/739,244 US8439861B2 (en) | 2007-04-24 | 2007-04-24 | Skin penetrating touch fasteners |
Publications (2)
Publication Number | Publication Date |
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US20080269670A1 true US20080269670A1 (en) | 2008-10-30 |
US8439861B2 US8439861B2 (en) | 2013-05-14 |
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ID=39564577
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US11/739,244 Active 2030-11-12 US8439861B2 (en) | 2007-04-24 | 2007-04-24 | Skin penetrating touch fasteners |
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US (1) | US8439861B2 (en) |
WO (1) | WO2008134237A1 (en) |
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US20130331792A1 (en) * | 2011-01-18 | 2013-12-12 | The Brigham And Women's Hospital, Inc. | Device and uses thereof |
WO2015016235A1 (en) * | 2013-07-30 | 2015-02-05 | Asti株式会社 | Microneedle array and microneedle array manufacturing method |
WO2017094996A1 (en) * | 2015-04-10 | 2017-06-08 | シーアンドテック株式会社 | Apparatus and method for manufacturing microneedle patch, and microneedle patch manufactured by same |
US9827406B2 (en) | 2012-10-05 | 2017-11-28 | Miguel A. Linares | Insertion tool for implanting a medicinal delivery device upon an internal organ |
JP2018011712A (en) * | 2016-07-20 | 2018-01-25 | 凸版印刷株式会社 | Percutaneous administration device |
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